tbuckley/cabot-search huggingface dataset:
Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity
Authors: Huaqing Jing, Yingzi Ren, Yue Zhou, Min Xu, Sona Krizkova, Zbynek Heger, Qiang Lu, Siyu Wang, Xiaoyang Liang, Vojtech Adam, Nan Li
Journal: Acta Pharmaceutica Sinica B (2023)

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.
Introduction of a novel chimeric active immunization mouse model of PLA2R1-associated membranous nephropathy
Authors: Nicola M. Tomas, Annabel Schnarre, Silke Dehde, Renke Lucas, Irm Hermans-Borgmeyer, Oliver Kretz, Sarah M.S. Koellner, Thorsten Wiech, Friedrich Koch-Nolte, Larissa Seifert, Tobias B. Huber, Gunther Zahner
Journal: Kidney International (2023)
Neonatal sepsis and antimicrobial resistance in Africa
Authors: Pui-Ying Iroh Tam, Adrie Bekker, Olufunke Bosede Bolaji, Gwendoline Chimhini, Angela Dramowski, Felicity Fitzgerald, Alemayehu Mekonnen Gezmu, John Baptist Nkuranga, Uduak Okomo, Alexander Stevenson, Jonathan P Strysko
Journal: The Lancet Child & Adolescent Health (2023)
An observational cohort study of histological screening for BK polyomavirus nephropathy following viral replication in plasma
Authors: Evert Cleenders, Priyanka Koshy, Elisabet Van Loon, Katrien Lagrou, Kurt Beuselinck, Graciela Andrei, Marta Crespo, Katrien De Vusser, Dirk Kuypers, Evelyne Lerut, Kris Mertens, Olga Mineeva-Sangwo, Parmjeet Randhawa, Aleksandar Senev, Robert Snoeck, Ben Sprangers, Claire Tinel, Amaryllis Van Craenenbroeck, Jan van den Brand, Marc Van Ranst, Geert Verbeke, Maarten Coemans, Maarten Naesens
Journal: Kidney International (2023)
Study of Late-Onset Stargardt Type 1 Disease
Authors: Catherina H.Z. Li, Jeroen A.A.H. Pas, Zelia Corradi, Rebekkah J. Hitti-Malin, Anne Hoogstede, Esmee H. Runhart, Patty P.A. Dhooge, Rob W.J. Collin, Frans P.M. Cremers, Carel B. Hoyng
Journal: Ophthalmology (2023)

Late-onset Stargardt disease is a subtype of Stargardt disease type 1 (STGD1), defined by an age of onset of 45 years or older. We describe the disease characteristics, underlying genetics, and disease progression of late-onset STGD1 and highlight the differences from geographic atrophy.Retrospective cohort study.Seventy-one patients with late-onset STGD1.Medical files were reviewed for clinical data including age at onset, initial symptoms, and best-corrected visual acuity. A quantitative and qualitative assessment of retinal pigment epithelium (RPE) atrophy was performed on fundus autofluorescence images and OCT scans.Age at onset, genotype, visual acuity, atrophy growth rates, and loss of external limiting membrane, ellipsoid zone, and RPE.Median age at onset was 55.0 years (range, 45-82 years). A combination of a mild and severe variant in ATP-binding cassette subfamily A member 4 (ABCA4) was the most common genotype (n = 49 [69.0%]). The most frequent allele, c.5603A→T (p.Asn1868Ile), was present in 43 of 71 patients (60.6%). No combination of 2 severe variants was found. At first presentation, all patients have flecks. Foveal-sparing atrophy was present in 33.3% of eyes, whereas 21.1% had atrophy with foveal involvement. Extrafoveal atrophy was present in 38.9% of eyes, and no atrophy was evident in 6.7% of eyes. Time-to-event curves showed a median duration of 15.4 years (95% confidence interval, 11.1-19.6 years) from onset to foveal involvement. The median visual acuity decline was -0.03 Snellen decimal per year (interquartile range [IQR], -0.07 to 0.00 Snellen decimal; 0.03 logarithm of the minimum angle of resolution). Median atrophy growth was 0.590 mm2/year (IQR, 0.046-1.641 mm2/year) for definitely decreased autofluorescence and 0.650 mm2/year (IQR, 0.299-1.729 mm2/year) for total decreased autofluorescence.Late-onset STGD1 is a subtype of STGD1 with most commonly 1 severe and 1 mild ABCA4 variant. The general patient presents with typical fundus flecks and retinal atrophy in a foveal-sparing pattern with preserved central vision. Misdiagnosis as age-related macular degeneration should be avoided to prevent futile invasive treatments with potential complications. In addition, correct diagnosis lends patients with late-onset STGD1 the opportunity to participate in potentially beneficial therapeutic trials for STGD1.The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Aire drives steroid hormone biosynthesis by medullary thymic epithelial cells
Authors: Matthew D. Taves, Kaitlynn M. Donahue, Jing Bian, Margaret C. Cam, Jonathan D. Ashwell
Journal: Science Immunology (2023)

Thymic epithelial cells (TECs) produce glucocorticoids, which antagonize negative selection of autoreactive thymocytes and promote a competent T cell antigen–specific repertoire. To characterize their source, we generated a knock-in reporter mouse in which endogenous Cyp11b1, the final enzyme in de novo production of active glucocorticoids, was fluorescently tagged with mScarlet. Here, we find that Cyp11b1 is expressed in medullary TECs (mTECs) but not cortical TECs or other cells in the thymus. A distinct characteristic of mTECs is the presence of Aire, a transcription factor that drives expression of tissue-restricted antigens (TRAs) important for establishing immune tolerance. Cyp11b1 expression was highest in Aire + mTECs, lower in post-Aire mTECs, and absent in mTECs of Aire -deficient mice. Transcriptomic analyses found that multiple enzymatic biosynthetic pathways are expressed specifically in mTECs and are also Aire dependent. In particular, we found that the thymus expresses messenger RNA for enzymes that catalyze production of many bioactive steroids and that glucocorticoids and sex steroids were secreted by cultured thymi. Expression of the transcripts for these genes and production of their final steroid products were markedly reduced in the absence of Aire. Thus, in addition to its well-established role in inducing TRAs that promote negative selection, Aire has an additional and contrary function of inducing glucocorticoids that antagonize negative selection, which together may expand and enhance the TCR repertoire. Furthermore, because Aire drives expression of multiple enzymes responsible for production of other non–gene-encoded bioactive molecules, it might have yet other roles in thymus development and function.
In vitro modeling of CD8 <sup>+</sup> T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40
Authors: Jennifer E. Wu, Sasikanth Manne, Shin Foong Ngiow, Amy E. Baxter, Hua Huang, Elizabeth Freilich, Megan L. Clark, Joanna H. Lee, Zeyu Chen, Omar Khan, Ryan P. Staupe, Yinghui J. Huang, Junwei Shi, Josephine R. Giles, E. John Wherry
Journal: Science Immunology (2023)

Identifying molecular mechanisms of exhausted CD8 T cells (T ex ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo T ex can be costly and inefficient. In vitro models of T ex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo T ex . We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate T ex subsets. By developing and benchmarking an in vitro model of T ex , then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of T ex .
Table of Contents
Authors: U De Giorgi, E Giunta, E Verzoni, G Procopio, A Desai, J Feldman, V Subbiah, B Kiesewetter, U Dafni, E De Vries, J Barriuso, G Curigliano, V González-Calle, M Galotti, B Gyawali, B Huntly, U Jäger, N Latino, L Malcovati, S Oosting, G Ossenkoppele, M Piccart, M Raderer, L Scarfò, D Trapani, C Zielinski, R Wester, P Zygoura, E Macintyre, N Cherny, K Chi, S Sandhu, M Smith, G Attard, M Saad, D Olmos, E Castro, G Roubaud, A Pereira De, Santana Gomes, E Small, D Rathkopf, H Gurney, W Jung, G Mason, S Dibaj, D Wu, B Diorio, K Urtishak, A Corral, P Francis, W Kim
Journal: Annals of Oncology (2023)
Evaluating the causal effect of circulating proteome on the risk of osteoarthritis-related traits
Authors: Yan Zhang, Jingyu Xie, Simin Wen, Peihua Cao, Wende Xiao, Jianwei Zhu, Shengfa Li, Zhiqiang Wang, Han Cen, Zhaohua Zhu, Changhai Ding, Guangfeng Ruan
Journal: Annals of the Rheumatic Diseases (2023)

This study aims to identify circulating proteins that are causally associated with osteoarthritis (OA)-related traits through Mendelian randomisation (MR)-based analytical framework.Large-scale two-sample MR was employed to estimate the effects of thousands of plasma proteins on 12 OA-related traits. Additional analyses including Bayesian colocalisation, Steiger filtering analysis, assessment of protein-altering variants and mapping expression quantitative trait loci to protein quantitative trait loci were performed to investigate the reliability of the MR findings; protein-protein interaction, pathway enrichment analysis and evaluation of drug targets were conducted to deepen the understanding and identify potential therapeutic targets of OA.Dozens of circulating proteins were identified to have putatively causal effects on OA-related traits, and a majority of these proteins were either drug targets or considered druggable.Through MR analysis, we have identified numerous plasma proteins associated with OA-related traits, shedding light on protein-mediated mechanisms and offering promising therapeutic targets for OA.
Dietary wheat amylase trypsin inhibitors exacerbate CNS inflammation in experimental multiple sclerosis
Authors: Victor F Zevallos, Nir Yogev, Judith Hauptmann, Alexei Nikolaev, Geethanjali Pickert, Valeska Heib, Nicola Fittler, Sebastian Steven, Felix Luessi, Manjusha Neerukonda, Claudia Janoschka, Ann-Marie Tobinski, Luisa Klotz, Ari Waisman, Detlef Schuppan
Journal: Gut (2023)

Objective Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis (MS). Design EAE was induced in C57BL/6J mice on standardised dietary regimes with defined content of gluten/ATI. Mice received a gluten and ATI-free diet with defined carbohydrate and protein (casein/zein) content, supplemented with: (a) 25% of gluten and 0.75% ATI; (b) 25% gluten and 0.19% ATI or (c) 1.5% purified ATI. The effect of dietary ATI on clinical EAE severity, on intestinal, mesenteric lymph node, splenic and central nervous system (CNS) subsets of myeloid cells and lymphocytes was analysed. Activation of peripheral blood mononuclear cells from patients with MS and healthy controls was compared. Results Dietary ATI dose-dependently caused significantly higher EAE clinical scores compared with mice on other dietary regimes, including on gluten alone. This was mediated by increased numbers and activation of pro-inflammatory intestinal, lymph node, splenic and CNS myeloid cells and of CNS-infiltrating encephalitogenic T-lymphocytes. Expectedly, ATI activated peripheral blood monocytes from both patients with MS and healthy controls. Conclusions Dietary wheat ATI activate murine and human myeloid cells. The amount of ATI present in an average human wheat-based diet caused mild intestinal inflammation, which was propagated to extraintestinal sites, leading to exacerbation of CNS inflammation and worsening of clinical symptoms in EAE. These results support the importance of the gut-brain axis in inflammatory CNS disease.
Letter to Editor. Re “de Leeuw SP, et al. Analysis of Serious Weight Gain in Patients Using Alectinib for ALK Positive Lung Cancer,” Semaglutide a Potential Treatment for Serious Weight Gain From ALK Tyrosine Kinase Inhibitors?
Authors: Alexandria T.M. Lee, Sai-Hong Ignatius Ou, Aaron Lisberg
Journal: Journal of Thoracic Oncology (2023)
Comment on “Leveraging NGS Data to Refine Immunotherapy Response Prediction in NSCLC: PD-L1 Copy Number, Tumor Mutation Burden, and Beyond”
Authors: Tae Hee Hong, Yeong Hak Bang, CheolYong Joe, Yoon-La Choi, Se-Hoon Lee
Journal: Journal of Thoracic Oncology (2023)
Remarkable Response to Immune Checkpoint Inhibitor Monotherapy in an EGFR-Mutant Pulmonary Adenocarcinoma Patient With 0% Expression of PD-L1
Authors: Tetsuo Fujita, Hiroyuki Amano, Makoto Nakamura, Satoshi Hirano, Sukeyuki Nakamura
Journal: Journal of Thoracic Oncology (2023)
Lung Cancer in Indonesia
Authors: Oke Dimas Asmara, Eric Daniel Tenda, Gurmeet Singh, Ceva Wicaksono Pitoyo, Cleopas Martin Rumende, Wulyo Rajabto, Nur Rahmi Ananda, Ika Trisnawati, Eko Budiyono, Harik Firman Thahadian, E. Christiaan Boerma, Achmad Faisal, David Hutagaol, Wuryantoro Soeharto, Fahmi Radityamurti, Erika Marfiani, Pradana Zaky Romadhon, Fathur Nur Kholis, Hendarsyah Suryadinata, Arto Yuwono Soeroto, Soehartati A. Gondhowiardjo, Wouter H. van Geffen
Journal: Journal of Thoracic Oncology (2023)
Rapid and effective treatment of chronic osteomyelitis by conductive network-like MoS2/CNTs through multiple reflection and scattering enhanced synergistic therapy
Authors: Liguo Jin, Shuilin Wu, Congyang Mao, Chaofeng Wang, Shengli Zhu, Yufeng Zheng, Yu Zhang, Zhaoyang Li, Zhenduo Cui, Hui Jiang, Xiangmei Liu
Journal: Bioactive Materials (2023)

Staphylococcus aureus (S. aureus)-infected chronic osteomyelitis (COM) is one of the most devastating infectious diseases with a high recurrence rate, often leading to amputation and even death. It is incurable by all the current strategies involving the clinical use of radical debridement and systemic intravenous antibiotics. Here, we reported on a microwave (MW)-assisted therapy for COM by constructing a heterojunction formed by flake nanoflower-shaped molybdenum disulfide (MoS2) and tubular carbon nanotubes (CNTs). This composite could achieve a combination of MW thermal therapy (MTT) and MW dynamic therapy (MDT) to accurately and rapidly treat COM with deep tissue infection. In vitro and in vivo experiments showed that MoS2/CNTs were effective in non-invasively treating S. aureus-induced COM due to the heat and reactive oxygen species (ROS) produced under MW irradiation. The mechanism of heat and ROS generation was explained by MW network vector analysis, density of states (DOS), oxygen adsorption energy, differential charge and finite element (FEM) under MW irradiation. Since the Fermi layer was mainly contributed by the Mo-4d and C–2P orbitals, MoS2/CNTs could store a large amount of charge and easily release more electrons. In addition, charge accumulation and dissipation motion were strong on the surface of and inside MoS2/CNTs because of electromagnetic hot spots, resulting in the spilling out of a great deal of high-energy electrons. Due to the low oxygen adsorption energy of MoS2/CNTs-O2, these high-energy electrons combined further with the adsorbed oxygen to produce ROS.
Table of Contents
Authors: Elise Brunsgaard, Yelena Wu, Douglas Grossman, Jonathan Kantor, Warren Heymann, Andrew Blauvelt, Barry Ladizinski, Vimal Prajapati, Vivian Laquer, Alison Fischer, Samantha Eisman, Xiaofei Hu, Tianshuang Wu, Brian Calimlim, Blair Kaplan, Yingyi Liu, Henrique Teixeira, John Liu, Kilian Eyerich, Bruce Strober, Carle Paul, Luis Puig, Mark Lebwohl, Katy White, Veerle Vanvoorden, Delphine Deherder, Natalie Nunez Gomez, Mei-Ju Ko, Wan-Chuan Tsai, Ping-Hsiu Tsai, Le-Yin Hsu, Kuo-Liong Chien, Hon-Yen Wu, Ida Heerfordt, Peter Philipsen, Jeppe Andersen, Linnea Langhans, Grethe Schmidt, Niels Morling, Hans Wulf, Brandon Beal, Jeremy Udkoff, Leora Aizman, Jeremy Etzkorn, John Zitelli, Christopher Miller, Thuzar Shin, Joseph Sobanko, David Brodland, Brent Doolan, Mark Lavallee, Ingrid Hausser, F Pope, Suranjith Seneviratne, Ingrid Winship, Nigel Burrows
Journal: Journal of the American Academy of Dermatology (2023)
Cost effectiveness review of text messaging, smartphone application, and website interventions targeting T2DM or hypertension
Authors: Ruben Willems, Lieven Annemans, George Siopis, George Moschonis, Rajesh Vedanthan, Jenny Jung, Dominika Kwasnicka, Brian Oldenburg, Claudia d’Antonio, Sandro Girolami, Eirini Agapidaki, Yannis Manios, Nick Verhaeghe, Natalya Usheva, Violeta Iotova, Andreas Triantafyllidis, Konstantinos Votis, Florian Toti, Konstantinos Makrilakis, Chiara Seghieri, Luis Moreno, Sabine Dupont, Leo Lewis, Djordje Djokic, Helen Skouteris
Journal: npj Digital Medicine (2023)

Abstract Digital health interventions have been shown to be clinically-effective for type 2 diabetes mellitus (T2DM) and hypertension prevention and treatment. This study synthesizes and compares the cost-effectiveness of text-messaging, smartphone application, and websites by searching CINAHL, Cochrane Central, Embase, Medline and PsycInfo for full economic or cost-minimisation studies of digital health interventions in adults with or at risk of T2DM and/or hypertension. Costs and health effects are synthesised narratively. Study quality appraisal using the Consensus on Health Economic Criteria (CHEC) list results in recommendations for future health economic evaluations of digital health interventions. Of 3056 records identified, 14 studies are included (7 studies applied text-messaging, 4 employed smartphone applications, and 5 used websites). Ten studies are cost-utility analyses: incremental cost-utility ratios (ICUR) vary from dominant to €75,233/quality-adjusted life year (QALY), with a median of €3840/QALY (interquartile range €16,179). One study finds no QALY difference. None of the three digital health intervention modes is associated with substantially better cost-effectiveness. Interventions are consistently cost-effective in populations with (pre)T2DM but not in populations with hypertension. Mean quality score is 63.0% (standard deviation 13.7%). Substandard application of time horizon, sensitivity analysis, and subgroup analysis next to transparency concerns (regarding competing alternatives, perspective, and costing) downgrades quality of evidence. In conclusion, smartphone application, text-messaging, and website-based interventions are cost-effective without substantial differences between the different delivery modes. Future health economic studies should increase transparency, conduct sufficient sensitivity analyses, and appraise the ICUR more critically in light of a reasoned willingness-to-pay threshold. Registration: PROSPERO (CRD42021247845).
IgG4-related cholangitis – a mimicker of fibrosing and malignant cholangiopathies
Authors: Remco Kersten, David C. Trampert, Toni Herta, Lowiek M. Hubers, Lucas J. Maillette de Buy Wenniger, Joanne Verheij, Stan F.J. van de Graaf, Ulrich Beuers
Journal: Journal of Hepatology (2023)

IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+ SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030
Authors: H.A. Parsons, T. Blewett, X. Chu, S. Sridhar, K. Santos, K. Xiong, V.G. Abramson, A. Patel, J. Cheng, A. Brufsky, J. Rhoades, J. Force, R. Liu, T.A. Traina, L.A. Carey, M.F. Rimawi, K.D. Miller, V. Stearns, J. Specht, C. Falkson, H.J. Burstein, A.C. Wolff, E.P. Winer, N. Tayob, I.E. Krop, G.M. Makrigiorgos, T.R. Golub, E.L. Mayer, V.A. Adalsteinsson
Journal: Annals of Oncology (2023)
GTM-decon: guided-topic modeling of single-cell transcriptomes enables sub-cell-type and disease-subtype deconvolution of bulk transcriptomes
Authors: Lakshmipuram Seshadri Swapna, Michael Huang, Yue Li
Journal: Genome biology (2023)

Abstract Cell-type composition is an important indicator of health. We present Guided Topic Model for deconvolution (GTM-decon) to automatically infer cell-type-specific gene topic distributions from single-cell RNA-seq data for deconvolving bulk transcriptomes. GTM-decon performs competitively on deconvolving simulated and real bulk data compared with the state-of-the-art methods. Moreover, as demonstrated in deconvolving disease transcriptomes, GTM-decon can infer multiple cell-type-specific gene topic distributions per cell type, which captures sub-cell-type variations. GTM-decon can also use phenotype labels from single-cell or bulk data to infer phenotype-specific gene distributions. In a nested-guided design, GTM-decon identified cell-type-specific differentially expressed genes from bulk breast cancer transcriptomes.